KR20180091007A - Vitamin Formulation - Google Patents

Abstract

This patent specification relates to solid particles comprising one or more fat soluble vitamins which are more stable upon compression into tablets.

Description

Vitamin Formulation

The present invention relates to a solid particle comprising, in a high-content, one or more fat soluble vitamins which are more stable upon compression into tablets. Furthermore, the particles are free of any components derived from animals and thus may be suitable for vegetarians.

Compressed tablets are a very useful method for administering fat-soluble vitamins. They are easy to ingest, easy to store, and good to handle.

When compressed tablets are produced, harsh conditions are applied. It is clear that certain pressures must be used to compress any formulation into tablet form. Thus, in general, there is a problem that the components that are part of the formulation used to be compressed exude and are no longer part of the tablet. In other words, tablets generally contain less fat soluble vitamins than compressed formulations in compressed tablets. In general, the content of the fat-soluble vitamin decreases gradually during storage of the compressed tablet.

Gelatine, commonly used in fat-soluble vitamin formulations, is generally not suitable for vegetarians because it is derived from animal sources.

Due to the importance of compressed tablets containing fat soluble vitamins, improved compressible formulations have always been needed.

Surprisingly, it has been found that such enhancement can be achieved by the addition of one or more non-reducing sugars to solid formulations used in the production of compressed tablets.

Therefore,

(i) at least 20% by weight, based on the total weight of the solid particles, of at least one fat soluble vitamin,

(ii) at least one emulsifier, and

(iii) at least one non-reducing sugar,

(SP). ≪ / RTI >

These solid particles exhibit better storage stability (of fat-soluble vitamins) when compressed into tablets.

In addition, it is also possible to produce solid particles only with the above three kinds of components.

Therefore,

(i) at least 20% by weight, based on the total weight of the solid particles, of at least one fat soluble vitamin,

(ii) at least one emulsifier, and

(iii) one or more non-

(SP '). ≪ / RTI >

A preferred non-reducing sugar is a non-reducing disaccharide; More preferably sucrose and / or trehalose, and most preferably trehalose.

Sucrose is a disaccharide combination of monosaccharide glucose and fructose having the formula C ₁₂ H ₂₂ O ₁₁ . It is commercially available from many sources.

Sucrose is often extracted and purified from human cane or beet.

Trehalose, also known as mycose or tremolose, is a natural alpha-linked disaccharide formed by an alpha, alpha-1,1-glucoside bond between two alpha -glucose units. There is an industrial process in which trehalose is derived from corn starch. Biological pathways for trehalose biosynthesis are known.

Trehalose is commercially available from a variety of sources

The amount of non-reducing sugar in the solid particles is 5 to 55% by weight based on the total weight of the solid particles. Preferably 10 to 50% by weight, based on the total weight of the solid particles; More preferably 15 to 45% by weight based on the total weight of the solid particles.

Accordingly, the present invention relates to solid particles (SP) or solid particles (SP ') comprising from 5 to 55% by weight, based on the total weight of the solid particles, of at least one non-reducing sugar.

Accordingly, the present invention relates to solid particles (SP) or (SP ') comprising from 10 to 50% by weight, based on the total weight of the solid particles, of at least one non-reducing sugar.

Accordingly, the present invention relates to solid particles (SP) or solid particles (SP ') comprising from 15 to 45% by weight, based on the total weight of the solid particles, of at least one non-reducing sugar.

The solid particles according to the present invention comprise at least one fat soluble vitamin.

Fat-soluble vitamins are vitamins A, D, E and K (as well as their derivatives).

In a preferred embodiment of the present invention, vitamin A and / or derivatives thereof (e.g., vitamin A acetate and vitamin A palmitate) are used.

Accordingly, the present invention relates to the use of a solid (SP), (SP '), (SP1) or (SP2) in which the fat soluble vitamin is a derivative of vitamin A and / or vitamin A (in particular vitamin A acetate or vitamin A palmitate) Particles SP4.

The solid particles according to the invention generally comprise from 20 to 75% by weight, preferably from 25 to 70% by weight, based on the total weight of the solid particles, of a fat soluble vitamin, based on the total weight of the solid particles.

(SP), (SP1), (SP2), (SP2), and the like, wherein the solid particles comprise 20 to 75 weight percent of the fat soluble vitamin (s) based on the total weight of the solid particles. , (SP3) or (SP4).

(SP), (SP1 '), (SP2), (SP2), and the like, wherein the solid particles comprise 25 to 70 weight percent of the fat soluble vitamin (s) based on the total weight of the solid particles. , (SP3), (SP4) or (SP5).

Further, the solid particles according to the present invention comprise at least one emulsifier. Any emulsifier that is commonly known and used may be used. Mixtures of emulsifiers as well as a single emulsifier may be used.

Suitable emulsifiers include modified starches for foods; Ascorbyl palmitate; pectin; Alginate; Carrageenin; Furcellaran; Dextrin derivatives; Cellulose and cellulose derivatives (such as cellulose acetate, methylcellulose, hydroxypropylmethylcellulose); Lignosulfonates; Polysaccharide gums (for example, gum acacia (= gum arabic), modified gum acacia, TIC gum, flaxseed gum, guti gum, tamarind gum and arabinogalactan); Gelatin (cattle, fish, pigs, poultry); Vegetable protein such as peas, soybeans, cassia beans, cotton, potatoes, sweet potatoes, cassava, rapeseed, sunflower, sesame, flaxseed, safflower, lentils, nuts, wheat, rice, corn, barley, rye, And sorghum); Animal proteins, including milk or whey proteins; lecithin; Polyglycerol esters of fatty acids; Monoglycerides of fatty acids; Diglycerides of fatty acids; Sorbitan esters; And sugar esters (as well as derivatives thereof).

Emulsifiers not derived from animal sources are preferred.

More preferably, it is a food modified starch, a polysaccharide gum and a vegetable protein.

The starch may be physically and chemically modified. Pregelatinized starches are examples of physically modified starches. Acid-modified, oxidized, crosslinked, starch ester, starch ether and cationic starch are examples of chemically modified starches.

The amount of emulsifier (s) in the solid particles is generally from 20 to 75% by weight, preferably from 25 to 65% by weight, based on the total weight of the solid particles, based on the total weight of the solid particles.

Accordingly, the present invention relates to the above-mentioned food composition, wherein said at least one emulsifier is a food modified starch; Ascorbyl palmitate; pectin; Alginate; Carrageenin; Furcellaran; Dextrin derivatives; Cellulose and cellulose derivatives (such as cellulose acetate, methylcellulose, hydroxypropylmethylcellulose); Lignosulfonates; Polysaccharide gums (e.g., gum acacia (= gum arabic), modified gum acacia, TIC gum, flaked gum, guti gum, tamarind gum and arabinogalactan); Gelatin (cattle, fish, pigs, poultry); Vegetable protein such as peas, soybeans, cassia beans, cotton, potatoes, sweet potatoes, cassava, rapeseed, sunflower, sesame, flaxseed, safflower, lentils, nuts, wheat, rice, corn, barley, rye, And sorghum); Animal proteins, including milk or whey proteins; lecithin; Polyglycerol esters of fatty acids; Monoglycerides of fatty acids; Diglycerides of fatty acids; Sorbitan esters; (SP), (SP1), (SP2), (SP3), (SP4), (SP5) or (SP5) SP6). ≪ / RTI >

(SP), (SP), (SP1), (SP2), (SP3), (SP4), (SP5), or (SP6), which are not derived from animal feedstuffs, ), ≪ / RTI > solid particles (SP7 ').

(SP), (SP), (SP1), (SP2), (SP3) and (SP3), wherein the at least one emulsifier is selected from the group consisting of food modified starches, polysaccharide gums and vegetable proteins. , (SP4), (SP5) or (SP6).

(SP), (SP '), (SP1), (SP2), and (SP2), wherein the amount of the emulsifier (s) in the solid particles is 20 to 70% by weight based on the total weight of the solid particles. , SP3, SP4, SP5, SP6, SP7, SP7 'or SP7 ".

(SP), (SP '), (SP1), (SP2), and (SP2), wherein the amount of the emulsifier (s) in the solid particles is 25 to 65 wt.% Based on the total weight of the solid particles. , SP3, SP4, SP5, SP6, SP7, SP7 'or SP7 ".

Furthermore, the solid particles may comprise additional components (adjuvants). Such adjuvants include, for example, antioxidants such as ascorbic acid or its salts, tocopherol (synthetic or natural), butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole (BHA) Ester, ascorbic acid ester of tert-butyl hydroxyquinoline, ethoxy queen and / or fatty acid); Stabilizers (such as xanthan gum, gel-forming agents such as gellan gum); Wetting agents (e.g., glycerin, sorbitol, polyethylene glycol); dyes; Spices; Fillers and buffers.

These adjuvants may be useful in the preparation of solid particles, their preparation, the final product (in which solid particles are used) and / or the final product.

These compounds may optionally be used in an amount of up to 15% by weight based on the solid particles.

(SP), (SP2), (SP3), (SP4), (SP5), (SP6) ), (SP7), (SP7 '), (SP7' '), (SP8) or (SP9).

Accordingly, the present invention is directed to a pharmaceutical composition wherein said adjuvant (or adjuvants) is an antioxidant (such as ascorbic acid or a salt thereof, tocopherol (synthetic or natural), butylated hydroxytoluene (BHT), ascorbyl palmitate, Ascorbic acid ester of anthol (BHA), propyl gallate, tert-butyl hydroxyquinoline, ethoxy queen and / or fatty acid); Stabilizers (such as xanthan gum, gel-forming agents such as gellan gum); Wetting agents (e.g., glycerin, sorbitol, polyethylene glycol); dyes; Spices; (SP11), wherein the solid particles (SP11) are selected from the group consisting of fillers and buffering agents.

According to the process for producing solid particles according to the present invention, it is also possible that the solid particles are coated with the powder used in the powder catch process. Such powders may be, for example, corn starch.

The amount of powder (especially of corn starch) may be up to 15% by weight based on the total weight of the powder coated particles. In general, the content of the powder coating is kept as low as possible so that an additional coating layer can be formed.

It is also possible to coat the solid particles with the coating layer. This layer can be made of any known and used coating material.

A suitable size of the solid particles of the present invention is 50 to 1000 mu m (preferably 100 to 800 mu m); This size is defined as the diameter of the longest dimension of the particle and is generally measured by known methods (e.g., laser diffraction).

All particle sizes of the solid particles according to the present invention are determined by laser diffraction techniques using "Mastersizer 3000 " of Malvern Instruments Ltd. of Great Britain. Further information on this particle size measurement can be found in, for example, "Basic principles of particle size analytics " Malvern Instruments Limited, Enigma Business Part, Grovewood Road, Malvern, Worcestershire, WR14 1XZ, UK) and the "Manual of Malvern particle size analyzer". Particular reference has been made to the user's manual "MAN 0096 1.0, 1994, November ". Unless otherwise stated, all particle sizes for the coarse particles of the solid particles according to the present invention have a Dv90 value determined by laser diffraction (volume diameter, 90% of the distribution down this point, 10% above). The particle size can be determined in the form of a dry (i.e., powder) or suspension. Preferably, the particle size of the solid particles according to the invention is determined as a powder.

In addition, the distribution of the particle size of the solid particles is not an essential feature of the present invention.

In addition, the shape of the solid particles is not an essential feature of the present invention. The shape may be spherical or any other shape (also a mixture of shapes). Generally, the particles are preferably spherical.

The particles can be prepared by any of the commonly known processes used for producing such particles (spray drying, spray chilling, etc.).

Methods for coating such small particles are well known. This is generally carried out by fluidized bed spray granulation, film coating or wet granulation.

The solid particles according to the invention are mainly used in the production of compressed tablets.

(SP), (SP), (SP2), (SP3), (SP4), (SP5) and (SP6) in the production of compressed tablets, , SP7, SP7 ', SP7 ", SP8, SP9, SP10 and / or SP11.

The pressure used to make the tablet is 5 kN or more.

The pressure used for preparing the tablets is generally 5 to 40 kN, preferably 10 to 40 kN, more preferably 15 to 40 kN.

Accordingly, the present invention is directed to a method of preparing a solid particle dispersion composition comprising at least one solid particle SP, SP ', SP 1, SP 2, ), SP7 '', SP8, SP9, SP10 and / or SP11 are compressed at a pressure of at least 5 kN.

Accordingly, the present invention is directed to a method of preparing a solid particle dispersion composition comprising at least one solid particle SP, SP ', SP 1, SP 2, ), (SP7 ''), (SP8), (SP9), (SP10) and / or (SP11) are compressed at a pressure of 5 to 40 kN.

Accordingly, the present invention is directed to a method of preparing a solid particle dispersion composition comprising at least one solid particle SP, SP ', SP 1, SP 2, ), SP7 '', SP8, SP9, SP10 and / or SP11 are compressed at a pressure of 10 to 40 kN.

Accordingly, the present invention is directed to a method of preparing a solid particle dispersion composition comprising at least one solid particle SP, SP ', SP 1, SP 2, ), SP7 '', SP8, SP9, SP10 and / or SP11 are compressed at a pressure of 15 to 40 kN .

It is also possible to add any additional materials (such as fillers, dyes, antioxidants, perfumes, etc.) to the solid particles according to the present invention before compressing the particles into tablets.

Accordingly, the present invention relates to a process (P1), wherein the process (P), (P '), (P' ') or (P' '') in which one or more additional elements are added.

The tablet may be a health supplement or a medicament. This depends on what is additionally added to the compressed tablet.

Further, the present invention is also directed to a process for the preparation of a solid particulate composition comprising at least one solid particle (SP), (SP '), (SP1), (SP2), (SP3), (SP4), (SP5), (SP6) '), (SP7' '), (SP8), (SP9), (SP10) and / or (SP11).

The invention is illustrated by the following examples. All temperatures are given in degrees Celsius, and all parts and percentages are by weight.

Example

Example 1 : Food modified starch and trehalose

370.6 g of deionized water was heated in a vessel to 60 < 0 > C to 65 < 0 > C. 316.75 g of food modified starch and 121.2 g of trehalose were added and the mixture was made to be a solution at 60 to 65 DEG C with stirring. The resulting solution was cooled to 50-55 < 0 > C and degassed for 1 hour. At this time, 190.82 g of an oil mixture (180.78 g vitamin A acetate, 5.02 g BHT and 5.02 g dl-alpha-tocopherol) was added to the matrix system and emulsified. The temperature of the process was always kept below 65 ° C. After emulsification the internal phase of the emulsion had an average particle size of about 272 nm (Dv (0.1) = 100 nm, Dv (0.5) = 272 nm, Dv (0.9) = 559 nm) Malvern 3000). After emulsification, the moisture of the emulsion determined by a halogen moisture analyzer (Mettler Toledo, type HR73-P) was checked and adjusted if necessary. Thereafter, 150 g of an emulsion was sprayed into a spray pan containing 1500 g of corn starch, using a rotary atomizing nozzle. The resulting particles were filtered from an excess of corn starch (150 to 600 mu m) and dried at room temperature using an air stream. The final product particle size after drying was 246 占 퐉 (Dv (0.1) = 198 占 퐉, Dv (0.5) = 246 占 퐉, Dv (0.9) = 303 占 퐉) on average by laser diffraction (Malvern 3000). Solid particles having the compositions listed in Table 1 were obtained.

Furtherance [weight%] Vitamin A acetate 2.8 Mio I. U / g 27.00 dl-alpha-tocopherol 0.75 BHT 0.75 Modified starch for food 47.31 Trehalose 18.19 Corn starch 4.00 water 2.00 gun 100.00

Example 2 : Food modified starch and trehalose

381 g of deionized water was heated in a vessel to 60 to 65 占 폚. 316.75 g of food grade modified starch and 122.2 g of trehalose were added and the mixture was made to be a solution while stirring at 60 to 65 ° C. The resulting solution was cooled to 50-55 < 0 > C and degassed for 1 hour. At this time, 190.78 g of vitamin A acetate was added to the matrix system and emulsified. The temperature of the process was always kept below 65 ° C. After emulsification the internal phase of the emulsion had an average particle size of about 333 nm (Dv (0.1) = 175 nm, Dv (0.5) = 333 nm, Dv (0.9) = 558 nm) ). After emulsification, the moisture of the emulsion determined by a halogen moisture analyzer (METTLER TOLEDO, type HR73-P) was checked and adjusted if necessary. Thereafter, 150 g of an emulsion was sprayed into a spray pan containing 1500 g of corn starch, using a rotary atomizing nozzle. The resulting particles were filtered from excess corn starch and dried at room temperature using an air stream (150-600 mu m). The final product particle size after drying was an average of 180 占 퐉 (Dv (0.1) = 180 占 퐉, Dv (0.5) = 240 占 퐉 and Dv (0.9) = 321 占 퐉) as measured by laser diffraction (Malvern 3000). Solid particles having the compositions listed in Table 2 were obtained.

Furtherance [weight%] Vitamin A acetate 2.8 Mio I. U / g 27.00 Modified starch for food 48.31 Trehalose 18.19 Corn starch 4.00 water 2.00 gun 100.00

Example 3 : Food modified starch and sucrose

370.6 g of deionized water was heated in a vessel to 60 < 0 > C to 65 < 0 > C. 317.4 grams of food grade modified starch and 122.1 grams of trehalose were added and the mixture was allowed to stir while stirring at 60-65 占 폚. The resulting solution was cooled to 50-55 < 0 > C and degassed for 1 hour. At this time, 197.3 g of an oil mixture (186.9 g vitamin A acetate, 10.4 g BHT) was added to the matrix system and emulsified. The temperature of the process was always kept below 65 ° C. After emulsification, the internal phase of the emulsion had an average particle size of about 276 nm (Dv (0.1) = 112 nm, Dv (0.5) = 276 nm, Dv (0.9) = 516 nm) ). After emulsification, the moisture of the emulsion determined by a halogen moisture analyzer (METTLER TOLEDO, type HR73-P) was checked and adjusted if necessary. Thereafter, 150 g of an emulsion was sprayed into a spray pan containing 1500 g of corn starch, using a rotary atomizing nozzle. The resulting particles were filtered from an excess of corn starch (150 to 600 mu m) and dried at room temperature using an air stream. The final product particle size after drying was 272 占 퐉 (Dv (0.1) = 197 占 퐉, Dv (0.5) = 272 占 퐉, Dv (0.9) = 377 占 퐉) as measured by laser diffraction (Malvern 3000). Solid particles having the compositions listed in Table 3 were obtained.

Furtherance [weight%] Vitamin A acetate 2.8 Mio I. U / g 27.00 BHT 1.50 Modified starch for food 45.86 Sucrose 17.64 Corn starch 5.00 water 3.00 gun 100.00

Example 4 : Sword acacia and trehalose

381 g of deionized water was heated in a vessel to 60 to 65 占 폚. 143.78 g of food grade modified starch and 287.56 g of trehalose were added and the mixture was made to be a solution at 60 to 65 DEG C with stirring. The resulting solution was cooled to 50-55 < 0 > C and degassed for 1 hour. At this time, 187.68 g of an oil mixture (177.80 g vitamin A acetate, 4.94 g BHT and 4.94 g dl-alpha-tocopherol) was added to the matrix system and emulsified. The temperature of the process was always kept below 65 ° C. After emulsification, the internal phase of the emulsion had an average particle size (Dv (0.1) = 215 nm, Dv (0.5) = 493 nm, Dv (0.9) = 987 nm) of about 493 nm and measurements were made by laser diffraction ). After emulsification, the moisture of the emulsion determined by a halogen moisture analyzer (METTLER TOLEDO, type HR73-P) was checked and adjusted if necessary. Thereafter, 150 g of an emulsion was sprayed into a spray pan containing 1500 g of corn starch, using a rotary atomizing nozzle. The resulting particles were filtered from an excess of corn starch (150 to 600 mu m) and dried at room temperature using an air stream. The final product particle size after drying was 234 占 퐉 (Dv (0.1) = 189 占 퐉, Dv (0.5) = 234 占 퐉, Dv (0.9) = 293 占 퐉) as measured by laser diffraction (Malvern 3000). Solid particles having the compositions listed in Table 4 were obtained.

Furtherance [weight%] Vitamin A acetate 2.8 Mio I. U / g 27.00 dl-alpha-tocopherol 0.75 BHT 0.75 Sword Acacia 21.83 Trehalose 43.67 Corn starch 4.00 water 2.00 gun 100.00

Example 5 : Stability in Compression Tablets

100 g of powder consisting of 27 g of vitamin A acetate particles (obtained in Example 1), 33.24 g of microcrystalline cellulose, 49.86 g of calcium phosphate and 0.2 g of magnesium stearate was mixed for 10 minutes. This final formulation was then compressed to a pressure of 35 kN. The tablets (usually disk-shaped; 0.2 g) were stored in a closed glass vial at room temperature and the vitamin A acetate content after 1, 7 and 35 days storage was determined.

For the purpose of showing the excellent properties of the particles according to the invention, a comparative example in which a sugar other than non-reducing sugar was used instead of trehalose or sucrose was also carried out. These comparative solid particles were prepared as described in Example 1.

The effect of using Trehalose is far superior to other plasticizers. This can be confirmed on figures 1, 2 and 3 (solid particles are listed in Tables 5 to 7. Concentrations of the components are the same as in Example 1).

The compressed tablets graph Composition of solid particles One Vitamin A acetate Modified starch for food Maltodextrin 12 BHT / Toko 2 Vitamin A acetate Modified starch for food Trehalose BHT / Toko 3 Vitamin A acetate Modified starch for food Sucrose BHT / Toko

The compressed tablets graph Composition of solid particles One Vitamin A acetate Modified starch for food Maltodextrin 20-23 BHT / Toko 2 Vitamin A acetate Modified starch for food Maltodextrin 12 BHT / Toko 3 Vitamin A acetate Modified starch for food Trehalose BHT / Toko

The compressed tablets graph Composition of solid particles One Vitamin A acetate Sword Acacia Maltodextrin 20-23 BHT / Toko 2 Vitamin A acetate Sword Acacia Maltodextrin 12 BHT / Toko 3 Vitamin A acetate Sword Acacia Trehalose BHT / Toko

Claims (10)

(i) at least 20% by weight, based on the total weight of the solid particles, of at least one fat soluble vitamin,
(ii) at least one emulsifier, and
(iii) at least one non-reducing sugar,
≪ / RTI > The method according to claim 1,
5 to 55% by weight, based on the total weight of the solid particles, of at least one non-reducing sugar (preferably trehalose). The method according to claim 1,
10 to 50 weight percent of at least one non-reducing sugar based on the total weight of the solid particles. 4. The method according to any one of claims 1 to 3,
Wherein the fat soluble vitamin is selected from the group consisting of vitamin A and derivatives thereof (e.g., vitamin A acetate or vitamin A palmitate). 5. The method according to any one of claims 1 to 4,
20 to 75% by weight, based on the total weight of the solid particles, of at least one fat soluble vitamin. 6. The method according to any one of claims 1 to 5,
25 to 70% by weight, based on the total weight of the solid particles, of at least one fat soluble vitamin. 7. The method according to any one of claims 1 to 6,
Based on the total weight of the solid particles, 20 to 70% by weight of at least one emulsifier, 8. The method according to any one of claims 1 to 7,
Wherein the at least one emulsifier comprises
Modified starch for food; Ascorbyl palmitate; pectin; Alginate; Carrageenin; Furcellaran; Dextrin derivatives; Cellulose and cellulose derivatives (such as cellulose acetate, methylcellulose, hydroxypropylmethylcellulose); Lignosulfonates; Polysaccharide gums (e.g., gum acacia (= gum arabic), modified gum acacia, TIC gum, flaxseed gum, guti gum, tamarind gum and arabinogalactan); Gelatin (cattle, fish, pigs, poultry); Vegetable protein such as peas, soybeans, cassia beans, cotton, potatoes, sweet potatoes, cassava, rapeseed, sunflower, sesame, flaxseed, safflower, lentils, nuts, wheat, rice, corn, barley, rye, And sorghum); Animal proteins, including milk or whey proteins; lecithin; Polyglycerol esters of fatty acids; Monoglycerides of fatty acids; Diglycerides of fatty acids; Sorbitan esters; And sugar esters (as well as derivatives thereof).
Solid particles. Use of the solid particles according to any one of claims 1 to 8 in the production of compressed tablets. A compressed tablet comprising at least one solid particle according to any one of claims 1 to 8.

Images